Alcohol has been for a long time a major health problem which affects a significant proportion of the population. This proposal is designed to study the effect of chronic ethanol administration on the ultrastructural, cytochemical and electrophysiological characteristics of glutamatergic synapses of the dentate fascia in lines of mice that were selectively bred for a differential CNS sensitivity to ethanol: the long-sleep (LS), the short-sleep (SS) and the heterogeneous (HS) mice. The target region will be the dentate fascia of the hippocampus because after chronic ethanol consumption a loss of dentate granule cells and dendritic spines was observed, together with a shrinkage of the dentate molecular layer. This indicates that dendrites, dendritic spines as well as axons and axon terminals of the perforant path are affected. A measure of the functional normalcy of the perforant path-dentate synapse will be its capacity to generate long-term potentiation upon tetanic stimulation of the perforant path. The importance of this experiment is not only in testing the normalcy of the synaptic system but also in the implication of the long-term potentiation in mnemonic functions. Its absence could be related to the damage of mnemonic processes observed following chronic ethanol consumption. The synapses of the dentate fascia use glutamate as a transmitter. In vitro glutamatergic synapses show an increase in glutamate binding accompanied by a considerable Ca++ displacement from synaptic membranes. In addition significantly lower accumulation of glutamate in synaptic vesicles was shown in the LS than in the SS mice. Therefore, ultrastructural parameters like the size and density of synaptic vesicles, the size of the postsynaptic density which harbors the synaptic receptors will be measured. Since biochemical changes observed in the synapses might not be coded in the ultrastructure but in the ultrastructural cytochemistry of the synapse, the distribution of Ca++ and organization of actin filaments will be studied employing the recently developed cytochemical methods. It is hoped that these multidisciplinary studies on the effect of chronic ethanol administration in lines of mice which differ in sensitivity to ethanol may be important in elucidating questions of practical and theoretical importance to the alcohol research.
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